Ladies and gentlemen, thank you for standing by, and welcome to the Geron Corporation Fourth Quarter Fiscal 2021 Earnings Call. All lines have been placed on mute to prevent any background noise. After the speakers' remarks, there will be a question-and-answer session. [Operator Instructions] Thank you. Olivia Bloom, you may begin your conference.

Good afternoon, everyone. Welcome to the Geron Corporation fourth quarter and year-end 2021 conference call. I'm Olivia Bloom, Geron's Chief Financial Officer. I'm joined today by Dr. John Scarlett, Geron's Chairman and Chief Executive Officer; Dr. Aleksandra Rizo, Geron's Executive Vice President and Chief Medical Officer; and Anil Kapur, Geron's Executive Vice President of Corporate Strategy and Chief Commercial Officer. Before we begin, please note that during the course of this presentation and question-and-answer session, we will be making forward-looking statements regarding future events, performance, plans, expectations and other projections including those relating to the therapeutic potential and potential regulatory approval of imetelstat, anticipated clinical and commercial events and related timelines, the sufficiency of Geron's financial resources and other statements that are not historical facts. Actual results and events could differ materially. Therefore, I refer you to the discussion under the heading Risk Factors in Geron's annual report on Form 10-K for the year ended December 31, 2021, which identifies important factors that could cause actual results to differ materially from those contained in the forward-looking statements. Geron undertakes no duty or obligation to update our forward-looking statements. And now, I will turn the call over to Dr. Scarlett. Chip?

Thanks, Olivia. Good afternoon everyone. Before reviewing our significant accomplishments of 2021 and even before discussing how we plan to build on those accomplishments in 2022 and beyond, I'd like to spend a moment putting into context why we believe imetelstat can potentially be such a transformative drug, especially in the treatment of hematologic malignancies. Next slide, please. As many of you know, telomeres and enzyme that adds length to the ends of chromosomes, thus allowing for continued cell proliferation. This enzyme is transiently expressed in normal hematopoietic stem cells during blood cell production. In contrast, telomeres continuously expressed in malignant hematopoietic stem and progenitor cells, leading to their uncontrolled proliferation. Imetelstat is an oligonucleotide, discovered and developed by Geron that inhibits telomeres and limits the proliferation of malignant cells where telomeres is continuously expressed. It thereby selectively induces apoptosis or killing of those malignant cells. This mechanism of action is unique and first-in-class. But what makes this drug so exciting and a very substantial potential value is that data from both Phase 2 trials in low-risk MDS and MF provides strong evidence of disease-modifying activity. Next slide, please. Here, we summarize that key evidence. In both Phase 2 trials, imetelstat's target engagement of telomeres led to a reduction of telomeres activity and depletion of malignant stem and progenitor cells in the bone marrow as evidenced by elimination of the malignant cells marked by molecular and cytogenetic abnormalities. Importantly, in our Phase 2 trial is the reduction in telomeres activity and depletion of malignant cells in the bone marrow was reinforced as clinically meaningful through the correlations of those biologic effects with clinical benefits such as anemia responses in MDS and in MF, reduction in bone marrow fibrosis as well as for the first time correlation with improvement in overall…

Thanks, Chip. In 2021, our clinical focus was on advancing our two Phase 2 trials in lower-risk MDS and refractory MF. This focus will continue in 2022 as we prepare for TLR for the IMerge Phase 3 trial and complete opening sites for the IMpactMF trial. Next slide. For IMerge Phase 3 today and for the rest of the year, the clinical team will concentrate on executing activities such as data cleaning to enable timely database lock and ensure top line results are reportable in early January 2023. Given the number of patients and clinical sites around the world, achieving these deliverables requires significant planning, organization and coordination amongst numerous parties with hands-on oversight by our internal team. In addition, we have implemented plans to ensure adequate resourcing for clinical operations, data management and medical review at our CRO and internally. Our Biostat team is preparing for the numerous statistical analysis and outputs that will be needed not only for a TLR but also for future regulatory submissions. We and our investigators from the IMerge study are eagerly looking forward to seeing the top line results. Given current global events, I would like to make a few comments on the impact of the ongoing conflict in Ukraine and Russia on this trial. We only have two patients at one site in Ukraine. We know that this site is currently close to patient visits and we do not know whether these two patients will be lost to a follow-up. In Russia, we have two patients at two sites and these sites are currently open to patient visits. At this time, we do not expect an impact to the timing of the TLR due to this conflict. Like all of you, we're closely monitoring this evolving situation. On to our second Phase…

Thanks, Alex, and good afternoon, everyone. I share Chip's and Alex's excitement as we get closer to the IMerge top line results. In my prepared remarks today, I'll first highlight imetelstat's expected product profile in lower-risk MDS and how this will differentiate the drug in the market. After that, I'll provide insights into the fast evolving myelofibrosis market. We believe that imetelstat can play a meaningful role in the treatment of patients in both indications. As I'll describe, these indications represent large addressable patient populations and significant commercial opportunities for Geron. Next slide. In lower-risk MDS, imetelstat’s product profile has been favorably received by practicing hematologist. Key attributes identified include imetelstat's ability to treat a broader set of patients, which includes both ring sideroblast-positive and ring sideroblast-negative subtypes as well as the durability of transfusion independence. In addition, imetelstat's unique mechanism of action and potential for disease modification resonated well with hematologists in our market service. Given that luspatercept's approval in lower-risk MDS is restricted to RS positive patients only, we are seeing a high level of awareness among practicing hematologist, for their patients RS status. We also hear their desire for more effective treatment options for lower-risk MDS patients who are RS negative. Thus, imetelstat’s ability to broadly treat patients across both RS-positive and RS-negative subtypes were seen as important by hematologists. Also, since responses to current treatment options are limited in duration, hematologists see durable transfusion independence for their patients. As such, the 24-week and the one-year transfusion independence data from our IMerge Phase 2 trial not only provide strong evidence for the durability of transfusion independence of imetelstat, but also were considered by hematologists to be highly clinically relevant for their patients. Next slide. Lower risk MDS represents approximately 70% of the total MDS patient population. Chronic…

Thanks, Anil. Next slide. As expected, overall operating expenses for the fourth quarter and full year 2021 were higher than the same period in 2020. Total operating expenses for the three and 12 months ended December 31, 2021, were $32 million and $115.4 million, respectively, compared to $23.3 million and $77.2 million for the same period in 2020. The increase in research and development expenses primarily reflects increased clinical development costs with our two ongoing Phase 3 clinical trials, higher imetelstat manufacturing costs for producing validation batches at contract manufacturers and higher personnel-related costs for additional headcount. The increase in general and administrative expenses primarily reflects new costs in connection with pre-commercial activities, including modernizing our internal infrastructure to support a potential commercial launch and higher legal costs. We ended the 2021 fiscal year with $212.7 million in cash and marketable securities, which we believe is sufficient to fund current operations through the end of the first quarter of 2023. For guidance on 2022, we expect non-GAAP total operating expenses to be in the range of approximately $140 million to $150 million. This guidance reflects expenses for supporting the two ongoing Phase 3 clinical trials as well as the new exploratory studies in frontline MF and AML. Finalizing validation batches of imetelstat at contract manufacturers to enable future production of imetelstat for clinical and commercial purposes, initial manufacturing for commercial inventory production, preparations for top line results and lower-risk MDS and future regulatory submissions, initial commercial readiness activities, projected increases in head count and larger interest payments due to higher outstanding debt. With that, I will now hand the call over to Chip to share our key upcoming corporate milestones. Chip?

Next slide, please. Thanks, Olivia. As I commented at the beginning of this call, 2021 was a year of critical execution and accomplishments for Geron as we drive towards significant future readouts from our Phase 3 trials and ultimately commercialization of imetelstat, 2022 is equally important. Next slide, please. Our expected key upcoming milestones include ensuring delivery of top line results for the Phase 3 IMerge lower-risk MDS trial in time for disclosure in early January of 2023. Assuming positive TLR, we are also preparing for a potential submission of the NDA in the first half of 2023, an MAA submission in the second half of 2023, and subsequent regulatory approval and commercialization in lower-risk MDS as early as the first half of 2024 in the U.S. As well, our team will continue executing on IMpactMF with opening the remaining selected sites by the end of the year. If we accomplish this, we expect that the planned interim analysis of IMpactMF may occur in 2024. Taking both separately and together, the upcoming readouts from these two Phase 3 registration trials have the potential to transform Geron from a late-stage development company into a commercial stage company and thus to realize our vision of Geron becoming a leader in the treatment of hematologic malignancies. Finally, we expect the new programs in our expanded pipeline to progress meaningfully this year and to begin the process of potential value accretion beyond our initial indications for imetelstat and possibly even beyond imetelstat itself. Looking forward, if we accomplish each of these important value-accreting milestones successfully, we expect imetelstat will change the treatment of lower-risk MDS and refractory MF with significant improvement for patients. Thanks very much for your interest in the company, and we'll be glad to take your questions. Operator, please open the call to questions.

[Operator Instructions] And your first question comes from Gil Blum with Needham & Company. Your line is open.

Hi and good afternoon. So maybe I had a quick question on myelofibrosis. So there's a bit of a shifting of the treatment landscape with the very recent approval of pacritinib. Do you think that it's going to extend the amount of time patients spend being refractory, i.e., living a little longer? Does that potentially increase the market for relapsed/refractory MF? Thank you.

Hi Gil, thanks very much. This is Chip. Can you hear me okay?

Yes.

Okay. Great. Okay. So I think I'm going to let Anil Kapur just take a first crack at that and others may have a few other comments. So the question was will the shifting with – will the pacritinib approval shift landscape in any way, and in particular, increase the number of patients who have a – who are on JAKi refractory. I think that was the question. Go ahead, Anil.

Yes. Sure. Thanks for the question, Gil. So pacritinib, as you know, was just approved for severely thrombocytopenic patients. These patients represent a small fraction of myelofibrosis patients, and it's different from the population that imetelstat can serve. And we welcome the addition of all of these new JAKi therapies for MF patients. And I think to answer your question, Gil, it all depends upon the patient population actually on pacritinib. So if the patient population on pacritinib is less than 50,000, which is their indicated label, that population will remain distinct from the population served by imetelstat. However, we think that this unmet need is very high, and we welcome the opportunity. But the general gist and I think I can say that for all therapies in development, is that over time, you will see this market significantly expand. And as we said, provide physicians with multiple choices across all lines, leading to a much, much larger second line, third line plus treatments in myelofibrosis, very similar to the dynamic is an example that we saw even in myeloma.

Thanks, Anil. Do you have any follow-up question on that?

Maybe to sharpen that last point a little further, it was my understanding that the thrombocytopenia as part of the disease progression as well as an outcome of the treatment of JAKis over time. And many patients live long enough, they will be confirmed thrombocytopenia. So it's kind of like a funnel, or your patients constantly like progress a bit more and more in thrombocytopenic. Am I misunderstanding that?

I'll let Aleksandra take that since she's the clinician on the call. Go ahead, Alex.

Yes, you have – you're correct in that saying that patients that progress over time, right, become thrombocytopenic. In addition to that, as we know the available or the approved JAK therapy at the moment also doesn't serve these patients or over time, these patients that – with time the patients that are treated with ruxolitinib, for example, become thrombocytopenic. So I think your conclusion is right there. And then these patients, as they progress, if they do have the appropriate number of platelet counts to be treated with imetelstat, they certainly are option for treatment or could potentially be an option for treatment with imetelstat.

Maybe I conclude some comments about this, Gil. I think the point that as we see it, is most of the patients who probably will end up on pacritinib at least early in the course would come from the frontline or near frontline, maybe – even possibly second line with low platelet counts. I think your question presupposes what will happen as patients become much more ill. And ultimately, patients become thrombocytopenic, neutropenic all on their own when their bone marrow fails. While it's certainly possible that some of those patients would benefit by the availability of the drug that is not limited by platelet counts. On the other hand, most of these patients are really failing JAKi therapy in other ways, symptomatic and otherwise. So I think that we will – I think that the dynamic will continue to evolve. And honestly, as Anil said, we do welcome these other entrants, especially into these areas that are particularly difficult patients to treat, but how exactly it's going to play out in numbers. I put my money on the entire market expanding as more and more patients become eligible for frontline therapy. That's just my point of view. Okay. May be we can move on to next question.

Yes. One additional question and then that will be for me. So do you guys have any time line on potential readout from the frontline combo study? We see a very interesting study?

Yes. Gil, I think, it's a little early to be commenting on that. All we know is that we're feeling comfortable that we'll begin the study or we'll open the site for enrollment in the first half of this year. But we don't know exactly how long it will take to ladder up the different dosing, right? So you have to take these studies quite slowly in the interest of safety, and that's been true for every combo study I've ever done really pretty much any indication. So the question will be, how long do we have to stick and what do we see in the way of adverse events as we add on. So I don't think there's a good expectation at the moment. I don't know if Aleksandra has any further commentary about that. Alex?

Yes. So thanks. I just wanted to make it clear that we expect to start the study in the second half of 2022. So that was something in my part of the script just because there is a bit more – and I’m sorry, this was – yes. So Chip was correct. I’m sorry, I moved to the investigator-led studies. So Chip is correct that the company-sponsored study and time to start enrollment in the first half. And as Chip said, we are first trying to safely combine the two drugs, and we are going to look for the safe dose. But with that said, right, it’s an open-label study, so we will be able to evaluate the potential efficacy of the two drugs as we go on, Gil. So that’s one addition that I wanted to give to Chip’s.

[Indiscernible]

Thanks very much Gil. Next question?

Your next question comes from the line of Stephen Willey with Stifel. Your line is open.

Hi, this is Ellen on for Steve. Thank you for taking the question. So maybe first one on the work that’s being done on the second-generation Telomeres inhibitor. I’m just wondering what the ideal profile that second-gen candidate would look like in your opinion? And what key improvements would be made compared to imetelstat? Thanks.

Yes, sure. I’ll take that one. So our number one choice and what we’re really going forward is an orally available small molecule that has all the usual benefits and one that would have all of the usual benefits of small molecule development, both in terms of manufacturing and also in terms of timing. And of course, the oral availability would be welcome in certain indications in certain types of utility. It’s a tall order. We started out with a couple of different scaffolds, but we’re still looking for a lead compound in that regard. I have a lot of hope here, but honestly, we’re not quite ready to report any specificity around this. And we will attempt to give a little bit more specificity once we have a lead compound. And I think we said in the past that will likely take us to the remainder of this year.

Okay. Great. Thanks. And then with regards to the frontline MF study, I know primary endpoint is really safety and the combinability of these two drugs. But just wondering from an efficacy perspective, total symptom score, kind of what the bar is for success here for moving the program forward?

Aleksandra, do you want to comment on that? Could you hear?

Sure. Yes. I hear it. And I just wanted to maybe start off by saying that really the enthusiasm of our side for this combination is really to bring the more disease modifying potential or disease modifying data that we have seen with imetelstat in relapse and refractory setting. So while – yes, we have to really look into the endpoints that are easy to evaluate like a TSS or MSBR. [ph] We will certainly be looking into other efficacy endpoints as well, potential CRs, PRs improvement of fibrosis as well. So it’s really going to be the totality of the data that we will be evaluating in this reminder one – Phase 1 study. So I think that’s kind of where we – how we are looking on this study.

Okay, great. Thank you for taking the questions and congrats on the progress.

Thank you.

Thank you.

[Operator Instructions] Your next question comes from the line of Joel Beatty with Baird. Your line is open.

Hi. Thanks for taking the questions. The first one is on the IMerge Phase 3 trial in MDS. Could you discuss what gives you confidence that the trial is sufficiently powered? I believe one example of something that could be successful as a 30% rate in the imetelstat arm versus 7.5% in the placebo arm. Could you talk to the – I realize it’s just an example, but could you talk to how realistic those numbers are?

Go ahead, Alex. Let’s trade up here.

Yes. So, Joel, I am not sure if I heard you well in the beginning, but I think you asked whether we have discussed these with the health authorities. And if that was the question...

No.

No. No, that was not at all, okay. I’m sorry, I really have a hard time hearing.

You’re having a little bit trouble hearing. Let me repeat the question and maybe I’ll take a crack, and then Alex, you can fill in. So Joel, I understood the question to be what gives us confidence in the outcome of the IMerge Phase 3 low-risk MDS study. And you cited the fact that we’ve commented in the past that we have a fairly conservative powering assumptions meaning that although we saw a 42% rate of 8-week TI in our Phase 2. We put into our powering assumptions a 30% rate, the very conservative rate. We also have noted that although in other trials, the placebo rate in, for example, MDS 005, which was a competitive study in a similar patient population that had a placebo rate of around I think it was 3% to 5% maximum. I think it was 4.5%. We’ve actually assumed first, statistical powering functions, to gain a very conservative 75%. So that we’ve talked about before. The other elements that make us feel really comfortable going into TLR are the similarity of the patient population. These are all patients who are – come from very, very similar populations. They’re non-del(5q). They all are relapsed and refractory to ESAs. They have – not all are naive to HMAs and to lenalidomide. This by the way, was a very similar patient population to the MEDALIST study for luspatercept, which was used for their approval. And then finally, I think that we feel – I’m very comfortable that the drug is being used in exactly the same way, starting dose of 7.5 milligrams per kilogram. We’ve refined of course, for the Phase 3 – during the course of Phase 2, we refined some of the dose modifications to be made during the study. But overall, I think we would say we have a very similar patient population, very similar treatment regimen and conservative statistics.

Great. That’s really helpful. Thanks for those points. Maybe moving on to a question on the IMpactMF trial. Are you able to discuss how the blinded event rate is comparing to the expectations going into the trial?

No, I don’t think we’re going to plan to do that. We are – you’re absolutely correct that the study is blinded. And at the – at this point in time, we don’t have any plans to discuss those – that event rate. It’s a long trial. We’ll see how things progress. So right now we’re focused on enrollment.

Okay, got it. It makes sense and thank you.

Okay, great. Thanks.

This concludes our Q&A session. I’d like to turn the call back to Dr. Scarlett for closing remarks.

Okay. Well, thanks very much for those excellent questions. Thanks, everybody, for joining us today. We really appreciate you taking the time to dial in and participate. We look forward to sharing the achievement of a lot of these milestones in the coming year. Stay healthy, everyone, and please, stay safe. Thank you. Bye-bye.

This concludes today’s conference call. You may now disconnect.